It is estimated that there are greater than 30 million cases of HIV infection and AIDS worldwide. There are steep rises of new infections in Eastern Europe and Latin America. In the Caribbean region, AIDS is the primary cause of death among young men and women. In Asia, some 7 million people are living with HIV. In industrialized countries, AIDS continues to have a significant impact in minority communities where complacency in the face of a major health risk is a growing problem (Report of the Executive Director of the Joint United Nations Program on HIV/AIDS (UNAIDS)).
HIV-1 is a retrovirus and thus utilizes RNA as its genomic message. Genome packaging is directed by a gag polyprotein produced in the host cell during late stages of the infectious cycle. An element of gag that is essential for genome recognition and the packaging of infectious RNA is a 55 amino acid nucleocapsid protein, NCp7. NC proteins of all known classes of retrovirus (except spumavirus) contain one or two copies of a retroviral zinc finger (ZF) motif, Cys(X)2Cys(X)4His(X)4Cys, where X is a variable amino acid and Zn2+ is coordinated to the invariant cysteine and histidine residues. As part of gag, NCp7 initiates genomic RNA encapsidation by recognition of a ca. 120 nucleotide sequence (psi-site or Ψ-site) of the RNA genome that contains four stem-loop (SL) sequences in its secondary structure (e.g., SL1, SL2, SL3, and SL4). Although multi-drug therapy of AIDS with inhibitors of HIV-1 reverse transcriptase and HIV-1 protease has dramatically delayed the onset of clinical disease and death due to AIDS, problems with this therapy are of increasing concern.
Currently available drugs for the treatment of HIV include six nucleoside reverse transcriptase (RT) inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir), three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz), and five peptidomimetic protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir and amprenavir). Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. many nucleoside analogs cannot be phosphorylated in resting cells, which is required for biological activity) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options.
Currently marketed HIV-1 drugs are dominated by either nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recently gained an increasingly important role in the therapy of HIV infections At least 30 different classes of NNRTI have been described in the literature (De Clercq) and several NNRTIs have been evaluated in clinical trials. Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazine derivatives (delavirdine) have been approved for clinical use. However, the major drawback to the development and application of NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue cell culture and in treated individuals, particularly those subject to monotherapy.
Furthermore, although work continues to advance in the development of vaccines against HIV-1, there is currently no vaccine available with proven effectiveness in humans (Amara et al, Science 2001 Apr. 6; 292(5514): 69-74). In addition, it is clear that there is a need for anti-HIV drugs targeted against novel viral targets that are less prone to the development of resistant virus. These facts stress the importance of methods for the identification of new anti-HIV molecules or compounds and HIV targets that possess the following properties: 1) anti-HIV molecules or compounds against the new targets would not exert cross-resistance with current anti-HIV drugs that affect other targets, 2) structural distinctiveness of the target compared to mammalian counterparts such that new molecule or compound selectivity can be achieved toward the HIV target, and 3) target structural and functional conservation so that mutational escape toward drug-resistance is minimized.